Deletion of TP53 (17p13) Is Associated with Poor Outcome for Newly Diagnosed High-Risk Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2982-2982
Author(s):  
Erming Tian ◽  
Joshua Epstein ◽  
Pingping Qu ◽  
Christoph Heuck ◽  
Frits van Rhee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosome 17 ◽  
University Of Arkansas ◽  
Newly Diagnosed ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction In multiple myeloma (MM), deletion of chromosome 17 p13 (del17p) is a poor prognostic feature. The percentage of cells carrying an abnormality has been reported to be important with thresholds of 20% being taken generally but thresholds as high as 60% being suggested more recently. We have reported previously in the Total Therapy (TT)-2 trial (NCT00083551) for newly diagnosed (ND) MM that del17p is an adverse prognostic factor (Blood 112: 4235). The TT3 trial (NCT00081939) incorporated Brtezomib into tandem Melphalan-based autotransplants with DT-PACE for induction/consolidation and Thalidomide and Dexamethasone for maintenance to treat patients with newly diagnosed MM. In more recent iterations of these trials following the introduction of novel agents in induction and during maintenance the impact of carrying del17p has not been studied. In particular we have stratified patients into low- or high-risk molecular subgroups based on the GEP-70 (TT4 protocol [NCT00734877] or TT5 protocol [NCT00869232], respectively). We have used interphase FISH (iFISH) to detect the presence of del17p in baseline bone marrow samples. Method The iFISH slides were prepared with bone marrow aspirates after removing erythrocytes. A specific TP53 probe at chromosome 17 arm p13 combined with a control probe for the ERBB3 locus (HER2, 17q12), in different colors, were hybridized to bone marrow cells. Myeloma PCs were identified by restricted Kappa or Lambda immunoglobulin light-chain staining. We investigated role of 20% cutoffs per ≥100 tumor cells for significant deletion of the TP53 probe. Kaplan-Meier analysis was used to estimate the distributions of overall survival (OS) and progression-free survival (PFS) during the follow-ups. OS was calculated from registration until the date of decease. PFS was similarly calculated, but also incorporated progressive disease as an event. Results We examined 709 baseline samples from TT3, 4, and 5 trials with the two probes at chromosome 17. Overall, 66 of 709 patients (9.3%) had deletion of TP53 locus, including 44 of the 591 (7.5%) of low-risk patients and 20 of the 118 (17.0%) high-risk patients (Table). The range of TP53-deleted cells among newly diagnosed patients is 20-99% (median=75%) overall; 35-100% (median=62%) in TT3-low-risk; 30-97% (median=80%) in TT3-high-risk; 21-99% (median=76%) in TT4; and 20-97% (median=81%) in TT5. Deletion of TP53 was associated with significant shorter OS and PFS in HR patients treated on TT3. The 3 year estimated OS of patients for TT3-HR with del17p was 33% compared with 56% for TT3-LR with del17p, and PFS of patients for TT3-HR with del17p was 25% compared with 51% for TT3-LR with del17p (Figure). The comparison of TT4 to TT5 continued showing short OS in HR patients treated on TT5. The 3 year estimated OS of patients for HRMM with del17p was 17% compared with 75% for TT5 patients without deletion (p=0.0008). But, del17p was neutral in LR patients treated on TT4 (Figure). Conclusion Since the introduction of novel agents during various stages of the disease and a focus on HRMM and LRMM defined by GEP70 we show that while TP53 deletion is an adverse prognostic factor for patients with HRMM it is no longer prognostically relevant in LRMM. Table 1. Patients with iFISH results GEP-70 riskLow ≤0.66 High >0.66 Deletion TP53 in 20-59% PCs (n/N [%]) Deletion TP53 in ≥60% PCs (n/N, [%]) Total TT3 (N=329) Low=256 9/329, [2.7%] 9/329, [2.7%] 18/329, [5.5%] High=73 3/329, [0.9%] 9/329, [2.7%] 12/329, [3.7%] TT4 (N=313) Low=313 5/313, [1.6%] 21/313, [6.7%] 26/313, [8.3%] High=0 0 0 0 TT5 (N=67) Low=22 2/67, [3.0%] 0 2/67, [3.0%] High=45 0 8/67, [11.9%] 8/67, [11.9%] Sum (N=709) Low=591 (83.4%) 14/709, [2.0%] 30/709, [4.2%] High=118 (16.6%) 3/709, [0.4%] 17/709, [2.4%] 66/709 (9.3%) Figure 1. Figure 1. Disclosures Tian: University of Arkansas for Medical Sciecnes: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Qu:Cancer Research and Biostatistics: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Millennium: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Hoering:Cancer Research and Biostatistics: Employment. Sawyer:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Weismann Institute: Honoraria; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

High Risk Multiple Myeloma Demonstrates Marked Spatial Genomic Heterogeneity Between Focal Lesions and Random Bone Marrow; Implications for Targeted Therapy and Treatment Resistance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 20-20 ◽  
Author(s):  
Niels Weinhold ◽  
Shweta S. Chavan ◽  
Christoph Heuck ◽  
Owen W Stephens ◽  
Ruslana Tytarenko ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Driver Mutations ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Clonal Heterogeneity ◽  
Advisory Committees ◽  
Site Specific

Abstract Introduction: Recent next generation sequencing studies have defined the mutation spectrum in multiple myeloma (MM) and uncovered significant intra-clonal heterogeneity, showing that clinically relevant mutations are often only present in sub-clones. Longitudinal analyses demonstrated that tumor clones under therapeutic pressure behave in a "Darwinian" fashion, with shifting dominance of tumor clones over time. Recently, stratification of clonal substructures in distinct areas of the tumor bulk has been shown for multiple cancer types. So far, spatial genomic heterogeneity has not been systematically analyzed in MM. This stratification in space is becoming increasingly important as we begin to understand the contribution of Focal Lesions (FL) to tumor progression and emergence of drug resistance in MM. We have recently shown that high numbers of FL are associated with gene expression profiling (GEP) defined high risk (HR). A comparison of GEP data of 170 paired random bone marrow (RBM) and FL aspirates showed differences in risk signatures, supporting the concept of spatial clonal heterogeneity. In this study we have extended the analysis by performing whole exome sequencing (WES) and genotyping on paired RBM and FL in order to gain further insight into spatial clonal heterogeneity in MM and to find site-specific single nucleotide variant (SNV) spectra and copy number alterations (CNA), which contribute to disease progression and could form the basis of adaptation of the tumor to therapeutic pressure. Materials and Methods: We included 50 Total Therapy MM patients for whom paired CD138-enriched RBMA and FL samples were available. Leukapheresis products were used as controls. For WES we applied the Agilent qXT kit and a modified Agilent SureSelect Clinical Research Exome bait design additionally covering the immunoglobulin heavy chain locus and sequences located within 1Mb of the MYC locus. Paired-End sequencing to a minimum average coverage of 120x was performed on an Illumina HiSeq 2500. Sequencing data were aligned to the Ensembl GRCh37/hg19 human reference using BWA. Somatic variants were identified using MuTect. For detection of CNA we analyzed Illumina HumanOmni 2.5 bead chip data with GenomeStudio. Subclonal reconstruction was performed using PhyloWGS. Mutational signatures were investigated using SomaticSignatures. The GEP70 risk signature was calculated as described previously. Informed consent in accordance with the Declaration of Helsinki was obtained for all cases included in this study. Results: Analyzing RBM and FL WES data, we detected between 100 and 200 somatic SNVs in covered regions, with approximately 30% of them being non-synonymous, and less than 5% stop gained or splice site variants. A comparison of paired RBM and FL WES data showed different extents of spatial heterogeneity. Some pairs had very similar mutation profiles with up to 90% shared variants, whereas others demonstrated marked heterogeneity of point mutations. We did not detect differences in mutational signatures between RBM and FL using the 'SomaticSignatures' package. We found site-specific driver mutations with high variant allele frequencies, indicating replacement of other clones in these areas. For example we observed a clonal KRAS mutation exclusively in the RBM, whereas a NRAS variant was only identified in the paired FL. The same holds true for large-scale CNAs (>1 Mb). We identified a case in which the high risk CNAs gain(1q) and del(17p) were only detectable in the FL. Further examples for site-specific CNAs were a del(10q21) and a gain(4q13) detected in FLs only. As a prominent pattern, we observed outgrowth of sub-clonal RBM CNAs as clonal events in the FL. Based on mutation and CNA data we identified different forms of spatial evolution, including parallel, linear and branching patterns. Of note, a stratified analysis by GEP70-defined risk showed that a more pronounced spatial genomic heterogeneity of SNVs and CNAs was associated with HR disease. Conclusion: We show that spatial heterogeneity in clonal substructure exists in MM and that it is more pronounced in HR. The existence of site-specific HR CNAs and driver mutations highlights the importance of heterogeneity analyses for targeted treatment strategies, thereby facilitating optimal personalized MM medicine. Disclosures Weinhold: University of Arkansas for Medical Sciences: Employment; Janssen Cilag: Other: Advisory Board. Chavan:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment; Foundation Medicine: Honoraria. Stephens:University of Arkansas for Medical Sciences: Employment. Tytarenko:University of Arkansas for Medical Sciences: Employment. Bauer:University of Arkansas for Medical Sciences: Employment. Peterson:University of Arkansas for Medical Sciences: Employment. Ashby:University of Arkansas for Medical Sciences: Employment. Stein:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. Johnson:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:Novartis: Research Funding; Onyx: Research Funding; Millennium: Research Funding; University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Davies:Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment; Janssen: Consultancy. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:University of Arkansas for Medical Sciences: Employment; MMRF: Honoraria; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1000-1000 ◽  
Author(s):  
Robert James Hayashi ◽  
Stuart S. Winter ◽  
Kimberly P. Dunsmore ◽  
Meenakshi Devidas ◽  
Brent Wood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
To Receive ◽  
Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Advanced Imaging and Targeted Myeloma Lesion Biopsies to Enhance Global Response Assessment and Evaluate Spatial Heterogeneity in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-22
Author(s):  
Sabrina L. Browning ◽  
Terri L. Parker ◽  
Noffar Bar ◽  
Tara Anderson ◽  
Madhav V. Dhodapkar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Advisory Board ◽  
Newly Diagnosed ◽  
Advanced Imaging ◽  
Advisory Committees

Background: Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm with significant genetic and biologic complexity. Limitations remain in our standard assessment of response to therapy, as random bone marrow biopsy may misrepresent the varied histologic and molecular features of this multifocal disease. Advanced imaging is crucial in evaluating bone and extramedullary (EM) lesions. We aim to refine global response assessment in MM, with incorporation of advanced imaging-guided lesion biopsies, to improve knowledge of residual tumor burden critical to patient outcomes. Methods: Patients ≥18 years of age with standard or high risk newly diagnosed clinical MM were eligible to participate in this study. Advanced imaging with positron emission tomography/computed tomography (PET/CT) or whole body magnetic resonance imaging (WB-MRI) based on access, standard bone marrow biopsy and aspiration, and targeted lesion biopsy occurred at enrollment and after 4 cycles of carfilzomib, lenalidomide, and dexamethasone (CRd). Carfilzomib was administered intravenously at a dose of 36 mg/m2 twice weekly, lenalidomide orally 25 mg daily days 1-21, and dexamethasone orally 40 mg weekly, with dose modifications as needed. Conventional clinical response, using IMWG Response Criteria (Kumar S et al, 2016), was assessed after each cycle of treatment. Results: An interim analysis was completed on 17 patients enrolled between June 2018 and March 2020, with 14 evaluable for global treatment response. Median age was 61 years (range, 43-76 years) and 82.4% of patients were male. 76.5% had Revised International Staging System (R-ISS) stage II or III disease and 58.8% had EM disease arising from bone (EM-B, 41.2%) or independently in soft tissue (EM-S, 17.6%). 70.6% of patients had at least one high risk feature at the time of diagnosis (Table 1). Of the 16 patients with conventional skeletal survey (CSS) at study entry, 68.8% had at least 1 myeloma-defining lesion on advanced imaging that was missed on CSS. Four patients had adequate sample from initial lesion biopsy for cytogenetics and fluorescence in situ hybridization (FISH), 3 of whom demonstrated discordant FISH results when compared to standard bone marrow samples. Clinical response rates after 4 cycles of CRd were notable with 85.7% of patients achieving ≥ very good partial response (VGPR) and 3 patients with stringent complete response (sCR) and minimal residual disease (MRD) negativity by flow cytometry with a sensitivity of 10-5. However, of the 12 patients with ≥ VGPR by conventional response assessment, 9 had residual disease on advanced imaging with PET/CT (2 patients), WB-MRI (6 patients), or total spine MRI (1 patient) (Figure 1). Repeat myeloma lesion biopsy was limited to 6 patients with targetable lesions after induction therapy, with diagnostic yield impacted by the presence of sclerotic tissue and insufficient marrow elements in some of the lesions sampled (Table 2). 85.7% of patients continued CRd or proceeded to high dose therapy and autologous stem cell rescue, with no patients transitioning directly to maintenance treatment after 4 cycles of CRd. At a median follow-up of 8 months, 14.3% (2/14) of patients have had progression of disease. Both individuals had residual lesions on imaging at end of treatment, despite one with flow MRD-negative sCR and normal FISH by standard assessment. There were no grade 4 serious adverse events or deaths. Conclusions: In our cohort of high risk newly diagnosed MM, CRd induction was potent and well-tolerated. While deep clinical responses were observed by conventional clinical assessment, two thirds of patients had persistent abnormalities on advanced imaging with concern that these sites could give rise to progressive MM. Our patients demonstrated spatial heterogeneity, highlighting the limitations of standard bone marrow evaluation. Use of advanced imaging and targeted lesion biopsies in response assessment enhances our understanding of tumor growth pattern in MM and consideration could be given to integrating these into clinical care when available. Current limitations of this study include a small number of patients with lesions amendable to repeat biopsy and their incomplete diagnostic yield. Ongoing investigation includes whole exome sequencing of paired bone marrow and focal lesion biopsies and application of a WB-MRI lesion scoring system to further augment this novel response assessment method. Disclosures Anderson: Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Dhodapkar:Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Kite: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Prebet:Jazz Pharmaceuticals: Consultancy, Research Funding. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Haims:Pfizer: Consultancy. Neparidze:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; GlaxoSmithKline: Research Funding; Janssen: Research Funding. OffLabel Disclosure: Carfilzomib has been shown to have significant anti-myeloma activity in relapsed myeloma. Phase I/II studies as well as one phase III study also showed favorable outcomes with carfilzomib-based regimens in newly diagnosed multiple myeloma, including in patients with high risk disease. We utilized an induction regimen with carfilzomib, lenalidomide, and dexamethasone given that patients enrolled in this study were required to have bone or soft tissue disease on advanced imaging, indicating a likely high risk feature with potentially aggressive disease biology. It has been shown that the combination of carfilzomib, lenalidomide, and dexamethasone is a safe regimen for patients with multiple myeloma. This combination is approved in the relapsed/refractory setting and included in NCCN guidelines for newly diagnosed multiple myeloma.

scholarly journals Value of Minimal Residual Disease (MRD) Monitoring Using Real-Time Quantitative PCR in Patients with Acute Promyelocytic Leukemia (APL) Treated with ATRA, ATO, +/- GO

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3851-3851
Author(s):  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Tapan M. Kadia ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Real Time ◽  
Quantitative Pcr ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Real Time Quantitative Pcr ◽  
Risk Patients ◽  
Standard Risk

Background: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to ATRA plus chemotherapy in the treatment of standard risk patients (pts) with newly diagnosed APL. MRD monitoring has been successfully utilized for the early identification of relapse. Qualitative PCR has been superseded with the more accurate real-time quantitative PCR (RQ-PCR) for MRD detection in APL. Methods: We reviewed pts with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without gemtuzumab ozogamicin (GO). GO was given to High risk pts (WBC >10 × 109/L) and pts with rising WBC. Real-time quantitative RT-PCR (RQ-PCR) was used to measure PML-RARα in bone marrow (BM) and peripheral blood (PB) specimens. We sought to determine the value of MRD monitoring in patients with APL treated with this regimen. Results: A total of 223 pts with APL have been followed from July 2002 to March 2019 with a total of 2007 samples (1622 BM, 385 PB) analyzed with a median number of samples of 8 per pt (range, 1-43). Median follow up is 55.6 months (range, 1-198). MRD positivity decreased over time on therapy; 218 pts (98%) were MRD positive after induction, while only 2 pts (1%) were positive after the first cycle of consolidation. Eight pts (3.5%) had positive MRD (all ≤0.1) during consolidation or after completing treatment but became negative after repeated MRD testing and none of them relapsed. Overall, seven pts relapsed (5 with high risk disease and 2 with low risk) and The median time to relapse after achieving CR was 9.4 months (range, 7.9-79.5).The time to the first relapse was between 7.9-12.4 months except for the pt who relapsed after 79.5 months (low risk pt), Among the high risk pts, molecular relapse preceded hematological relapse by 3.7 weeks (range, 2.1-4.1). There was a correlation between quantitative PCR values on PB and BM samples obtained concomitantly (r2=0.67, p=0.048). Conclusions: MRD monitoring may be useful for early detection of relapse in pts with high risk APL within first year after completion of therapy. Late molecular relapse is very rare and does not justify universal monitoring especially in standard risk patients. These data support the lack of need for MRD monitoring after completion of consolidation in pts with standard risk APL treated with ATRA plus ATO. Table Disclosures Kantarjian: Novartis: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Kadia:Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding. Jabbour:BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Borthakur:Incyte: Research Funding; Merck: Research Funding; Strategia Therapeutics: Research Funding; Janssen: Research Funding; GSK: Research Funding; Agensys: Research Funding; Oncoceutics, Inc.: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Polaris: Research Funding; NKarta: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Cantargia AB: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Daver:Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Celgene: Consultancy; Glycomimetics: Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding.

Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients <65 Years: Results of a Randomized Phase III Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3069-3069 ◽  
Author(s):  
Antonio Palumbo ◽  
Federica Cavallo ◽  
Izhar Hardan ◽  
Barbara Lupo ◽  
Valter Redoglia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
High Dose Melphalan

Abstract Abstract 3069FN2 Background: High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients. Aims: In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years. Methods: All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat. Results: Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43). Conclusions: PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting. Disclosures: Palumbo: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Upfront 28-Day Metronomic Therapy for High-Risk Multiple Myeloma (HRMM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1843-1843 ◽  
Author(s):  
Sharmilan Thanendrarajan ◽  
Daisy V. Alapat ◽  
Maurizio Zangari ◽  
Carolina Schinke ◽  
Christoph Heuck ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Proliferation Index ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Metronomic Therapy

Abstract Introduction: Despite major advances in MM therapy with the inclusion of novel agent combinations for induction prior to and after autotransplant-supported high-dose melphalan, the 15% of patients with GEP-defined HRMM continue to fare poorly with PFS and OS not exceeding 2 and 3 years, respectively. This poor outcome has not been improved with less dose-intense and more dose-dense Total Therapy 5. Having previously reported on 16-day metronomic therapy with low-dose doxorubicin (DOX) and cisplatin (DDP) plus VTD (Papanikolaou, Haematologica), we explored further extension of such metronomic treatment to 28 days (metro-28) also in newly diagnosed HRMM patients. Patients and Methods: All patients signed a written informed consent and data analysis was approved by our IRB. In the outpatient setting, a single cycle of metro-28 comprised DOX and DDP each at 1.0mg/m2/d for 28d by continuous infusion (CI), along with VTD (bortezomib 1.0mg/m2 on days 1-4, 7-10, 13-16, 19-22, 25-28; DEX 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; thalidomide 50-100mg/d x 28d; some patients also received vincristine [VCR] at a flat daily dose of 0.07mg/d x 28d by CI. Results: Fourteen patients were initiated on metro-28. Their characteristics included age >=65y in 12; albumin <3.5g/dL in 8; B2M >5.5mg/L in 7; cytogenetic abnormalities [CA] were present in 10; GEP70 HRMM in 9/13; PR subgroup in 8/13 (Table 1). The median follow up is 11mo. As portrayed in Figure 1A, no patient has died; the 6mo PFS estimate was 85% (Figure 1B); responses included CR in 3/14, VGPR in 7/14 and PR in 10/14 (Figure 1C); and the PR duration estimate at 6mo is 80% (Figure 1D). Of interest, GEP70 scores morphed to low risk in 3/13. Vascular density (CD34) decreased markedly in most patients evaluated. Toxicities were minor; myelosuppression was virtually absent; alopecia was not encountered. Subsequent salvage therapies included repeat metro-28, combination chemotherapy (PACMED) and autotransplants. Conclusion: We conclude that metro-28 is a promising and safe strategy for elderly patients with HRMM, and we hypothesize an anti-angiogenic mechanism of action in addition to direct anti-MM effects. Table 1. Patient characteristics Factor n/N (%) Age >= 65 yr 12/14 (86%) Albumin < 3.5 g/dL 8/14 (57%) B2M >= 3.5 mg/L 9/12 (75%) B2M > 5.5 mg/L 7/12 (58%) Hb < 10 g/dL 10/14 (71%) Cytogenetic Abnormalities 10/14 (71%) CA within 1 Year of Therapy 10/14 (71%) CA within 90 Days of Therapy 9/14 (64%) GEP 70-Gene High Risk 9/13 (69%) GEP PR Subgroup 8/13 (62%) GEP Proliferation Index >= 10 7/13 (54%) GEP Centrosome Index >= 3 7/13 (54%) n/N (%): n- Number with factor, N- Number with valid data for factor Figure 1. Figure 1. Disclosures Thanendrarajan: University of Arkansas for Medical Sciences: Employment. Alapat:University of Arkansas for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Onyx: Research Funding; Millennium: Research Funding; Novartis: Research Funding. Schinke:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Foundation Medicine: Honoraria; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Rosenthal:Cancer Research and Biostatistics: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Davies:Janssen: Consultancy; Onyx: Consultancy; University of Arkansas for Medical Sciences: Employment; Millenium: Consultancy; Celgene: Consultancy. Morgan:MMRF: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; CancerNet: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment.

The Impact of Combination Chemotherapy and Tandem Stem Cell Transplant on Clonal Substructure and Mutational Pattern at Relapse of MM

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 372-372 ◽  
Author(s):  
Christoph Heuck ◽  
Niels Weinhold ◽  
Erich Allen Peterson ◽  
Michael Bauer ◽  
Caleb K. Stein ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Advisory Board ◽  
Proliferation Index ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Advisory Committees ◽  
The Impact

Abstract Introduction: Next generation sequencing of over 800 newly diagnosed multiple myeloma (NDMM) cases has established the mutational landscape and key cancer driver pathways. The mutational basis of relapse has not been systematically studied. Two previous studies (Keats et al.; Bolli et al.) identified 4 patterns of clonal evolution. Neither study included uniformly treated patients and looked at the impact of therapy on clonal structure at relapse. Understanding the mutational patterns underlying relapse and how they relate to specific therapies is crucial in order to improve MM outcomes, especially for high-risk (HR) MM. In this study we compare the clonal structure at presentation (PRES) and at relapse (REL), after exposure to Total Therapy (TT). Materials and Methods: We studied 33 pairs of tumor samples collected at PRES and REL. 9 patients were treated on TT2, 13 on TT3, 10 on TT4 and 1 on TT5-like regimen. Eleven patients had HR disease at PRES. DNA was extracted from CD138+ selected cells from random bone marrow aspirates. Germline controls were obtained from leukapheresis products. Whole exome sequencing libraries were prepared using the Agilent qXT kit and the Agilent SureSelect Clinical Research Exome kit with additional baits covering the Ig and MYC loci. All samples were sequenced on an Illumina HiSeq2500 to a median depth of 120x. Sequencing data were aligned to the Ensembl GRCh37/hg19 human reference using BWA. Somatic variants were called using MuTect. Translocations were identified using MANTA. Copy number variations were inferred using TITAN. Gene expression profiles (GEP), generated using the Affymetrix U133plus2 microarray, were available for all tumor samples. Nonnegative matrix factorization (NMF) was used to define mutation signatures. Results: The median time to progression was 30 months with a median follow up of 9.5 years. 22 cases achieved a complete remission (CR) or near CR. There were 11 cases of HR at PRES. Of the 22 cases with low risk (LR) MM, 7 relapsed with HR disease. There were on average 478 SNVs per sample at PRES and 422 at REL. All but 2 cases had evidence of new mutations at REL. There were no consistent patterns or number of mutation associated with REL or GEP-defined risk. Patients of the MF molecular subgroup had more mutations compared to other molecular subgroups (657 vs. 379) and were enriched for mutations with an APOBEC signature. We did not detect any mutation signature consistent with chemotherapy-induced alterations, providing evidence that TT itself does not cause additional mutations. Primary recurrent IgH translocations called by MANTA were confirmed by GEP data. A number of new translocations were identified , several only at REL. In particular we demonstrate a case with a newly acquired MYC translocation at relapse, indicating that it contributed to progression. We identified 5 patterns of clonal evolution (Figure 1): A) genetically distinct relapse in 3 patients, B) linear evolution in 8 patients, C) clonal selection in 9 patients, D) branching evolution in 11 patients, and E) stable clone(s) in 2 patients. Patterns A (distinct) and B (linear) were associated with low risk and longer survival, whereas patterns D (branching) and E (stable) were associated with high risk and shorter time to relapse and overall survival (Table 1). Conclusion: This is the first study to systematically analyze the pattern of clonal evolution using NGS in patients treated with combination chemotherapy and tandem ASCT. We identified 5 patterns of evolution, which correlate with survival. We identified 3 cases with a loss of the original clone and emergence of a new clone, suggesting high effectiveness of Total Therapy for those patients. The persistence of major clones despite multi agent chemotherapy in most other cases supports a concept of a tumor-initiating cell population that persist in a protective niche, for which new therapies are needed. Table 1. Pattern of Evolution GEP70 Pres.(high risk: ≥0.66) Proliferation Index Pres. GEP70 Rel.(high risk: ≥0.66) Proliferation Index Rel Mean OS Mean TTR A: distinct (n=3) -0.690 -3.34 -0.015 2.04 8.18 5.00 B: linear (n=8) -0.171 -0.34 0.618 9.22 5.70 4.05 C: selection (n=9) 0.366 3.20 0.569 6.97 3.95 2.64 D: branching (n=11) 0.710 5.17 1.173 11.15 3.84 2.21 E: stable (n=2) 1.532 7.42 1.124 2.54 0.96 0.35 Pres.: Presentation; Rel.: Relapse; OS: Overall Survival; TTR: Time to Relapse Figure 1. Patterns of Relapse Figure 1. Patterns of Relapse Disclosures Heuck: Foundation Medicine: Honoraria; Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. Weinhold:Janssen Cilag: Other: Advisory Board; University of Arkansas for Medical Sciences: Employment. Peterson:University of Arkansas for Medical Sciences: Employment. Bauer:University of Arkansas for Medical Sciences: Employment. Stein:University of Arkansas for Medical Sciences: Employment. Ashby:University of Arkansas for Medical Sciences: Employment. Chavan:University of Arkansas for Medical Sciences: Employment. Stephens:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Johnson:University of Arkansas for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Millennium: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Matin:University of Arkansas for Medical Sciences: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Epstein:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Weismann Institute: Honoraria; MMRF: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Integrative Network Analysis of Newly Diagnosed Multiple Myeloma Identifies a Novel RNA-Seq Based High Riskgene Signature

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3285-3285
Author(s):  
Alessandro Lagana ◽  
Deepak Perumal ◽  
David Melnekoff ◽  
Ben Readhead ◽  
Brian Kidd ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Kaplan Meier ◽  
Risk Patients ◽  
Equity Ownership

Abstract High-risk Multiple Myeloma (MM) is characterized by unresponsiveness to multiple therapies, rapid disease progression and short overall survival, and may be significantly different from relapsed MM, where aggressiveness is usually a result of drug-resistance associated to clonal selection. Several gene expression-based signatures have been proposed in the past years, however the identification of high-risk patients at diagnosis still represents a challenge. Next generation high-throughput sequencing technologies have enabled a deeper insight into cancer genomes and transcriptomes at an unprecedented level of detail. MMRF CoMMpass is a longitudinal, prospective observational study, started in 2011, that aims to collect and analyze sequencing and clinical data from >1,000 MM patients at initial diagnosis and at relapse. CoMMpass is a real world observational study and, as such, reflects the therapeutic heterogeneity seen across patient populations and provides a unique opportunity to correlate molecular profiles, genomic alterations and clinical characteristics of MM with treatment outcome. Here we present a network approach to identify high-risk myeloma patients developed using next generation sequencing data from 450 patients in the IA7 release of CoMMpass. We generated MMNet, an integrated network model of newly diagnosed myeloma based on RNA-seq, Whole-Exome (WXS) and Whole-Genome (WGS) data correlated with clinical outcomes. MMNet consisted of 37 modules of coexpressed genes, that were further characterized by functional enrichment analysis and correlation with clinical traits and genomic alterations, i.e. somatic mutations and copy number alterations inferred from WGS and WXS data. A total of 89 progression/death events have been reported for the cohort within the second year since the beginning of the study. Cox regression analysis identified a module of co-expressed genes whose over-expression was significantly correlated with early relapse (<2yr) (HR 1.75, 95%CI = 1.169-2.614, p=0.005). The module was also associated to stage III R-ISS, high clonality (>4 clones) and high mutational burden, as well as higher percentage of plasma cells in both bone marrow and peripheral blood, which are traits associated with high-risk disease. Module expression was also up regulated in patients with mutations in TP53 and MAX, 13q deletion and 1q amplification. We further narrowed down the signature to 286 genes (the MMNet-286 signature) strongly correlated with time to Event Free Survival (EFS) (r = -0.81, p = 0). This gene-set was significantly enriched for several pathways including Cell Cycle, DNA repair and Homologous Recombination (q < 0.01). Cox regression analysis showed that the two clusters induced by MMNet-286 discriminated between lower and higher risk patients with respect to EFS (HR = 2.22, 95% CI = 1.505-3.295, p = 4.007e-5) (Fig. 1). The prognostic value of MMNet-286 was confirmed on two independent datasets: Broyl-2010 (HR = 1.76, 95% CI = 1.182-2.642, p = 0.005) and Shaughnessy-2006 (HR = 2.65, 95% CI = 1.746-4.031, p = 2.03e-6) (Fig. 2 and 3). The Broyl-2010 dataset consisted of 275 samples from newly diagnosed myeloma patients included in the HOVON65/GMMG-HD4 trial (GSE19784). The Shaughnessy-2006 dataset consisted of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658). Comparison of MMNet-286 with previous high risk signatures and disease classes revealed an overlap of five genes with the UAMS-70 signature, twelve genes with the EMC-92 signature and fifteen genes with the set of up-regulated genes in the UAMS PR class, for which the coexpression module was enriched. In Conclusion, our results demonstrate the advantages of employing integrated network models to identify prognostic features based on next generation sequencing data from large cohort of patients. Applications of the MMNet-286 signature include the generation of a prognostic assay (i.e. NanoString) for the identification of high-risk patients. Future work will aim at validation of the signature in larger cohorts from CoMMpass and other studies. Figure 1 Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 1. Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 2 Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 2. Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Disclosures Chari: Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ontomics, Inc.: Equity Ownership; AstraZeneca: Speakers Bureau; NuMedii, Inc.: Patents & Royalties; Personalis: Patents & Royalties.

scholarly journals Efficacy of Induction Thearapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3294-3294 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Risk Patients ◽  
Standard Risk

Abstract Background : Lenalidomide, bortezomib and dexamethasone (RVD) has been shown to be a well-tolerated and efficacious induction regimen in newly diagnosed myeloma patients. Two large randomized phase III trials show an overall response rate (ORR) >95% (Durie et al, Attal et al) supporting this combination regimen. We have conducted a retrospective analysis utilizing our institutional data of 1000 patients treated with RVD induction therapy at the Winship Cancer Institute of Emory University. Methods: 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 years (range 16-83). Other notable patient characteristics include: M/F 54.3%/45.6%; W/AA 56.4%/34%; ISS I and II/III 54%/17%; Isotype IgG/IgA/FLC 59.1%/19%/15.8%; standard risk/high risk 72%/28%. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype. A total of 835 patients (83.5%) underwent autologous stem cell transplant (ASCT) upfront after attaining at least a partial response with induction therapy, and 165 patients (16.5%) were offered deferred transplant. Among the patients that opted for deferred transplant, 56 of these patients (33.9%) underwent ASCT at first relapse with a median time to transplant of 30 months (3-96). 755 (75.5%) of patients received risk-stratified maintenance therapy following transplant. Evaluation of responses to induction therapy for the entire cohort show an ORR 97.3% with ≥VGPR of 68% post-induction therapy. Response rates 100 days post-transplant show an ORR 98% with 30.7% of patients achieving a sCR. Response rates are summarized in table 1. Median PFS was 63 months for the entire cohort, and 72 months for standard risk patients (61.75-82.25) versus 37 months for the high-risk patients (30.84-43.16), p<0.001. Median OS has not been reached at median of 38 months follow up (Figure 1). Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction. These results illustrate both the activity of this induction regimen with impressive response rates and long-term outcomes in both standard and high risk patients. Disclosures Hofmeister: Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Specific Identification of High Risk Disease Using Molecular Profiling By Mymap (Myeloma MLPA and translocation PCR) of 1,036 Cases

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2981-2981
Author(s):  
Martin F Kaiser ◽  
Eileen Mary Boyle ◽  
Brian A Walker ◽  
Dil B Begum ◽  
Paula Proszek ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Intensive Therapy ◽  
Intermediate Risk ◽  
University Of Arkansas ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Younger Patients ◽  
Specific Identification

Abstract Introduction Identifying molecular high risk myeloma remains a diagnostic challenge. We previously reported co-segregation of >1 adverse lesion [t(4;14), t(14;16), t(14;20), gain(1q), del(17p)] by iFISH to specifically characterise a group of high risk patients (Boyd et al., Leukemia 2012). However, implementation of this approach is difficult using FISH because of its technical limitations. We recently developed and validated a novel high-throughput all-molecular testing strategy against FISH (MyMaP- Myeloma MLPA and translocation PCR; Kaiser MF et al., Leukemia 2013; Boyle EM et al., Gen Chrom Canc 2015). Here, we molecularly characterised 1,036 patients from the NCRI Myeloma XI trial using MyMaP and validated the co-segregation approach. Materials, Methods and Patients Recurrent translocations and copy number changes were assayed for 1,036 patients enrolled in the NCRI Myeloma XI (NCT01554852) trial using CD138+ selected bone marrow myeloma cells taken at diagnosis. The trial included an intensive therapy arm for younger and fitter and a non-intense treatment arm for elderly and frail patients. Analysis was performed using MyMaP, which comprises TC-classification based multiplex qRT-PCR and multiplex ligation-dependent probe amplification (MLPA; MRC Holland). Median follow up for the analysis was 24 months. Results Adverse translocations [t(4;14), t(14;16), t(14;20)] were present in 18.2% of cases, del(17p) in 9.3%, gain(1q) in 34.5% and del(1p32) in 9.4% of cases. All adverse lesions were associated with significantly shorter PFS and OS by univariate analysis (P <0.05 for all). Of the 1,036 analysed cases, 13.5% carried >1 adverse lesion, 33.9% had one isolated adverse lesion and 52.6% had no adverse lesion. Presence of >1, 1 or no adverse lesion was associated with a median PFS of 17.0, 23.9 and 30.6 months (P =3.0x10-9) and OS at 24 months of 67.9%, 75.0% and 86.0% (P =1.8x10-7), respectively. Del(1p) was associated with shorter PFS and OS for the intensive, but not for the non-intensive therapy arm and was independent of the co-segregation model by multivariate analysis regarding OS (P =0.006). We thus included del(1p) as an additional adverse lesion in the model for younger patients. The groups with >1 (19.4% of cases), 1 (31.1%) and no adverse lesions (49.5%) were characterised by median PFS of 19.4, 29.4 and 39.1 months (P =1.2x10-10) and median 24-months survival of 73.8%, 86.4% and 91.5% (P =1.4x10-6), respectively. Hazard Ratio for >1 adverse lesion was 3.0 (95% CI 2.1-4.1) for PFS and 3.8 (95% CI 2.2-6.5) for OS. By multivariate analysis, co-segregation of adverse lesions was independent of ISS for PFS/OS in the entire group of 1,036 cases and in the intensive treatment arm. We integrated adverse lesions and ISS into a combined model defining High Risk (>1 adv les + ISS 2 or 3; 1 adv les + ISS 3) and Low Risk (no adv les + ISS 1 or 2; 1 adv les + ISS 1) and the remainder as Intermediate Risk. The High Risk, Intermediate Risk and Low Risk groups of the total cohort included 11.2%, 41.2% and 41.6% of cases with median PFS of 15.8, 19.8 and 35.2 months (P <2.2x10-16) and median OS at 24 months of 62.9%, 73.7%, and 90.7% (P =4.0x10-14), respectively. Integration of ISS into the model for younger patients resulted in highly specific identification of a High Risk group (15.6% of cases) with HR 3.8 (CI 2.6-5.4) for PFS and 6.2 (CI 3.3-11.6) for OS. Conclusions Co-segregation analysis of adverse genetic lesions is a specific molecular risk stratification tool which has now been validated in two large independent trials including a real-world population of all age groups (UK MRC Myeloma IX; NCRI Myeloma XI; total 1,905 patients). MyMaP is a validated all-molecular analysis approach that makes the otherwise technically challenging assessment of multiple genetic regions by FISH accessible using standard laboratory equipment without bioinformatics requirements. Disclosures Kaiser: BristolMyerSquibb: Consultancy; Chugai: Consultancy; Janssen: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Pawlyn:Celgene: Honoraria, Other: Travel support; The Institute of Cancer Research: Employment. Jones:Celgene: Other: Travel support, Research Funding. Savola:MRC Holland: Employment. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Sanofi: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Gregory:Celgene: Honoraria; Janssen: Honoraria. Davies:Takeda-Milenium: Honoraria; Onyx-Amgen: Honoraria; Celgene: Honoraria; University of Arkansas for Medical Sciences: Employment. Jackson:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Morgan:Weisman Institute: Honoraria; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; CancerNet: Honoraria; MMRF: Honoraria.

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